Orunite - instructions for use, dose, side effects, contraindications

Itraconazole is a synthetic broad-spectrum antifungal agent, a triazole derivative. Inhibits the synthesis of ergosterol cell membrane of fungi, which causes the antifungal effect of the drug.

Itraconazole is active against infections caused by dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), yeast-like fungi and yeast (Cryptococcus neoformans, Pityrosporum spp., Candida spp., including C.albicans, C.glabrata and C.krusei), Aspergillus spp., Histoplasma spp., Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea spp., Cladosporium spp., Blastomyces dermatitidis, as well as other yeast and mold fungi.

Pharmacokinetics:

When administered orally, the maximum bioavailability of itraconazole is noted when taking capsules immediately after a dense meal. The maximum concentration in the plasma is reached within 3-4 hours after ingestion. Excretion from plasma is biphasic with a terminal elimination half-life of 1 to 1.5 days. At long reception the equilibrium concentration is reached within 1-2 weeks. The equilibrium concentration of itraconazole in the plasma 3-4 hours after taking the drug is 0.4 μg / ml (100 mg once daily), 1.1 μg / ml (200 mg once a day) and 2, 0 μg / ml (200 mg when taken twice a day). Itraconazole at 99.8 % is bound by plasma proteins. The accumulation of the drug in keratin tissues, especially in the skin, is about 4 times higher than the accumulation in the plasma, and the rate of its removal depends on the regeneration of the epidermis.

Unlike plasma concentrations that are not detectable within 7 days after cessation of therapy, therapeutic concentrations in the skin persist for 2-4 weeks after discontinuation of a 4-week course of treatment. Itraconazole is found in the nail keratin within one week after the start of treatment and is maintained for at least 6 months after the completion of the 3-month course of therapy. Itraconazole is also determined in sebum and to a lesser extent in sweat.

Itraconazole is well distributed in tissues that are prone to fungal lesions. Concentrations in the lungs, kidneys, liver, bones, stomach, spleen and muscles were two to three times higher than the corresponding concentrations in the plasma. Therapeutic concentrations in the tissues of the vagina persist for 2 days after the end of the 3-day course of treatment at a dose of 200 mg per day, and 3 days after the end of a one-day course of treatment at a dose of 200 mg twice a day.

Itraconazole is metabolized by the liver with the formation of a large number of metabolites. One such metabolite is hydroxy-itraconazole, which is comparable with itraconazole antifungal action in vitro. The antifungal concentrations of the preparation, determined by the microbiological method, were approximately 3 times higher than those measured by HPLC. Excretion with feces is from 3 to 18% of the dose.Kidney excretion is less than 0.03% of the dose. Approximately 35% of the dose is excreted as metabolites in urine for 1 week.

Indications:

Orunite in capsules is indicated for the treatment of the following diseases:

- dermatomycosis;

- fungal keratitis;

- onychomycosis caused by dermatophytes and / or yeast and mold fungi;

- Systemic mycoses: systemic aspergillosis and candidosis, cryptococcosis (including cryptococcal meningitis), histoplasmosis, sporotrichosis, paracoccidioidomycosis, blastomycosis and other systemic or tropical mycoses;

- Candidomycosis with skin or mucosal lesions, including vulvovaginal candidiasis;

- deep visceral candidiasis;

- pityriasis lichen.

Contraindications:

Orunite in capsules is contraindicated:

- patients with individual hypersensitivity to the drug or its constituents;

- bOrunite women should be prescribed only if the expected benefit for a woman exceeds the potential risk to the fetus. Women of childbearing age who take Orunit need to use adequate methods of contraception throughout the course of treatment until the onset of the first menstrual period after it is completed.

- telfenadine, astemizole, misolastine, cisapride, dofetilide, quinidine, pimozide metabolizing with the participation of an enzyme CYP3A4 HMG-CoA reductase inhibitors such as simvastatin and lovastatin, triazolam and midazolam It can not be taken concomitantly with Orunite (see also section "Interactions with other drugs").

Carefully:Children's age, severe heart failure, liver disease (including those accompanied by liver failure).

Pregnancy and lactation:

Based on the results of preclinical studies and in connection with the fact that studies on the use of itraconazole in pregnant women have not been conducted, itraconazole should be prescribed to pregnant women only with life-threatening systemic fungal infections, when the potential benefit for a woman justifies the possible risk to the fetus.

Since a small amount of itraconazole is excreted in the mother's milk, the expected benefit of taking itraconazole must be compared with the risk for the baby during breastfeeding. In case of doubt, breast-feeding should not be.

Dosing and Administration:

For optimal absorption of the drug, it is necessary to take Orunite in capsules immediately after meals.

Capsules should be swallowed whole.

Indication	Dose	Duration
Vulvovaginal candidiasis	200 mg twice a day or 200 mg once a day	1 day 3 days
Peregrine lichen	200 mg once a day	7 days 15 days
Dermatomycosis smooth skin	200 mg once a day 100 mg once a day	7 days 15 days
Fungal keratitis	200 mg once a day	21 day
Lesions of highly keratinized areas of the skin, such as hands and feet, require additional treatment for 15 days at 100 mg per day.
Oral candidiasis	100 mg once a day	15 days
Bioavailability of itraconazole for oral administration may be reduced in some patients with impaired immunity, for example, in patients with neutropenia, AIDS patients or organ transplants. Therefore, a double dose increase may be required.

Onychomycosis

Pulse therapy (see table)

One course of pulse therapy is a daily intake of 2 capsules Orunit twice a day (200 mg twice a day) for one week.

Two courses are recommended for the treatment of fungal lesions of the nail plates of the brushes. For treatment of fungal lesions of the nail plates of the feet, three courses are recommended (see table).The gap between the courses, during which you do not need to take the drug, is 3 weeks.

Clinical results will become evident after the end of treatment, as the nails grow.

Localization of onychomycosis

1 st

ned.

2nd

ned.

3rd

ned.

4th

ned.

5th

ned.

6th

ned.

7th

ned.

8th

ned.

9th

ned.

Lesions of the nail plates of the feet with or without defeat of the nail plates of the brushes

1st

course

Weeks free from reception of Orunite

2 nd

course

Weeks free from reception of Orunite

3rd

course

Lesion of the nail plates of brushes

1st

course

Weeks free from reception of Orunite

2 nd

course

Continuous treatment:

Two capsules per day (200 mg once a day) for 3 months.

Excretion of Orunite from the skin and nail tissue is slower than from the plasma. Thus, optimal clinical and mycological effects are achieved in 2-4 weeks after the end of treatment for skin infections and 6-9 months after the end of treatment for nail infections.

Systemic mycoses (the recommended dosages vary depending on the type of infection)

Indication

Dose

Average

Duration

Remarks

Aspergillosis

200 mg once a day

2-5 months

Increase the dose to 200 mg twice a day for invasive or disseminated disease

Candidiasis

100-200 mg once a day

from 3 weeks to 7 months

Cryptococcosis (except meningitis)

200 mg once a day

from 2 months to 1 year

Supportive therapy (cases of meningitis)
200 mg once a day

Cryptococcal meningitis

200 mg twice daily

Histoplasmosis

from 200 mg once a day to 200 mg twice daily

8 months

Sporotrichosis

100 mg once a day

3 months

Paracoccidioidomycosis

100 mg once a day

6 months

Chromomycosis

100-200 mg once a day

6 months

Blastomycosis

from 100 mg once a day to 200 mg twice daily

6 months

Pediatric Use

Since clinical data on the use of itraconazole in capsules in children is not enough, it is recommended to use itraconazole Only if the possible benefit exceeds the potential risk.

Side effects:

The most frequently reported adverse reactions in connection with the use of itraconazole were reactions from the gastrointestinal tract, such as dyspepsia, nausea, abdominal pain and constipation.

In addition, there were: anorexia headache, fatigue, reversible increase in the activity of "liver" enzymes, cholestatic jaundice,hepatitis, menstrual irregularities, dizziness and allergic reactions (such as itching, rash, hives and angioedema), peripheral neuropathy, Stevens-Johnson syndrome, alopecia, hypokalemia, edema, congestive heart failure and pulmonary edema, dark-colored urine, hypercreatininaemia.

In very rare cases, using Orunite developed severe toxic liver damage, including cases of acute hepatic insufficiency with a fatal outcome.

Overdose:

No data available. In case of an accidental overdose, supportive measures should be used. During the first hour, wash the stomach and, if necessary, assign Activated carbon. Itraconazole not excreted by hemodialysis.

There is no specific antidote.

Interaction:

1. Medicines that affect the metabolism of itraconazole.

The interaction of itraconazole with rifampicin, rifabutin and phenytoin was studied. Simultaneous use of itraconazole with these drugs, which are potential inducers of hepatic enzymes, is not recommended.Investigations of interaction with other inducers of hepatic enzymes, such as carbamazepine, phenobarbital and isoniazid, were not carried out, however, similar results can be assumed.

As itraconazole mainly metabolized by enzyme CYP3A4, potential inhibitors of this enzyme can increase the bioavailability of itraconazole. Examples are ritonavir, indinavir, clarithromycin and erythromycin.

2. The effect of itraconazole on the metabolism of other drugs.

Itraconazole can inhibit the metabolism of enzyme-cleavable drugs CYP3A4. The result of this can be an increase or prologue of their action, including side effects. After discontinuation of treatment, the levels of itraconazole in the plasma decrease gradually depending on the dose and duration of treatment (see section "Pharmacokinetics ").

Examples of such medicines are:

Drugs that can not be administered simultaneously with itraconazole:

terfenadine, astemizole, misolastine, cisapride, triazolam and midazolam, dofetilide, quinidine, pimozide, HMG-CoA reductase inhibitors such as simvastatin and lovastatin;
calcium channel blockers can have a negative inotropic effect, which can enhance the same effect as itraconazole. With the simultaneous administration of itraconazole and calcium channel blockers, care must be taken, as the metabolism of calcium channel blockers can be reduced.

Preparations, in the appointment of which it is necessary to monitor their concentration in the plasma, the effect, side effects

In the case of simultaneous administration with itraconazole dose of these drugs, if necessary, should be reduced:

Poral anticoagulants;
andHIV protease inhibitors, such as ritonavir, indinavir, saquinavir;
Mr.Some anticancer drugs, such as alkaloids Barvinka pink, busulfan, docetaxel, trimetrexate;
Renzyme-cleaved CYP3A4 calcium channel blockers such as dihydropyridine and verapamil;
Mr.Some immunosuppressive agents: ciclosporin, tacrolimus, sirolimus;
dOther drugs: digoxin, carbamazepine, buspirone, alfentanil, alprazolam, brotisolam, rifabutin, methylprednisolone, ebastine, reboxetine.

Interactions between itraconazole and zidovudine and fluvastatin were not detected.

There was no effect of itraconazole on the metabolism of ethinylestradiol and norethisterone.

3. Effect on protein binding.

Research in vitro demonstrated a lack of competition between itraconazole and drugs such as imipramine, propranolol, diazepam, cimetidine, indomethacin, tolbutamide and sulfamethazine for their association with plasma proteins.

Special instructions:

- It was found that itraconazole possesses negative inotropic effect. There have been reports of cases of heart failure associated with Orunite. Orunite should not be taken to patients with chronic heart failure or having a history of the disease, unless the potential benefit far exceeds the potential risk. When assessing the benefit-risk ratio individually, factors such as the severity of the indications, the dosage regimen, and individual risk factors for heart failure should be taken into account.

Risk factors include the presence of heart disease,such as ischemic heart disease or valve lesions; serious lung diseases, such as obstructive pulmonary disease; renal failure or other diseases accompanied by edema. Such patients should be informed about the signs and symptoms of heart failure. Treatment should be conducted with caution, while it is necessary to observe the patient for symptoms of congestive heart failure. When they appear, the reception of Orunite must be stopped.

- Calcium channel blockers can have a negative inotropic effect, which can enhance the similar effect of itraconazole; itraconazole can reduce the metabolism of calcium channel blockers. Caution should be exercised when concomitantly taking itraconazole and calcium channel blockers.

- With reduced acidity of the stomach: the absorption of itraconazole is impaired. Patients taking antacid preparations (for example, aluminum hydroxide), it is recommended to use them not earlier than 2 hours after taking Orunit capsules. Patients with achlorhydria or using H₂-gystamine blockers or proton pump inhibitors, it is recommended to take Orunite capsules with acidic beverages.

- In very rare cases, when applying Orunite developed severe toxic liver damage, including cases of acute hepatic insufficiency with a lethal outcome. In most cases, this occurred with patients who already had liver disease, in patients receiving systemic therapy, having other serious medical conditions, and also in patients receiving other drugs with hepatotoxic effect. In some patients, there were no obvious risk factors for liver damage. Several such cases occurred in the first month of therapy, and some in the first week of treatment. In this regard, it is recommended to regularly monitor liver function in patients receiving itraconazole therapy.

Patients should be warned about the need to immediately contact their doctor if symptoms occur that suggest hepatitis, namely: anorexia, nausea, vomiting, weakness, abdominal pain and darkening of the urine.In the case of such symptoms it is necessary to immediately stop therapy and conduct a study of liver function. Patients with increased activity of liver enzymes or liver disease in the active phase, or with transferred toxic liver damage when taking other medications should not be prescribed Orunite treatment, except when the expected benefit justifies the risk of liver damage. In these cases it is necessary during the treatment to monitor the activity of "liver" enzymes.

- Dysfunction of the liver: Itraconazole it is metabolized primarily in the liver. The half-life of itraconazole in patients with cirrhosis is slightly increased. Bioavailability of the drug for oral administration is somewhat reduced in patients with cirrhosis of the liver. In this case, it may be necessary to adjust the dose. With a duration of intake of more than one month, liver function monitoring is necessary.

- Impaired renal function: In patients with renal insufficiency, the bioavailability of itraconazole can be reduced. In this case, it may be necessary to adjust the dose.

- Treatment should be discontinued when Neuropathy, which can be associated with the reception of Orunit capsules.

- No data about cross-over-hypersensitivity to itraconazole and other azole antifungal agents. Orunite in capsules should be administered with caution to patients with hypersensitivity to other azoles.

- In patients with impaired immunity (AIDS, after organ transplantation, neutropenia) may require an increase in dose.

Effect on the ability to drive transp. cf. and fur:

Not observed.

Form release / dosage:Capsules, 100 mg.

Packaging:

For 5.6 or 15 capsules in the outline package.

By 1, 2 or 3 contour mesh packs of 5 or 6 capsules, or 1 circuit pack of 15 capsules together with instructions for use are placed in a pack of cardboard

Storage conditions:

In a dry place, protected from light and out of reach of children, at a temperature not exceeding above 25 ° С.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:P N002631 / 01

Date of registration:17.07.2008

Expiration Date:Unlimited

The owner of the registration certificate:OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Manufacturer: & nbsp

OBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSC Russia

Representation: & nbspOBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSCOBOLENSKOE PHARMACEUTICAL ENTERPRISE, CJSCRussia

Information update date: & nbsp14.06.2017

Illustrated instructions

Instructions

Indication	Dose	Average Duration	Remarks
Aspergillosis	200 mg once a day	2-5 months	Increase the dose to 200 mg twice a day for invasive or disseminated disease
Candidiasis	100-200 mg once a day	from 3 weeks to 7 months
Cryptococcosis (except meningitis)	200 mg once a day	from 2 months to 1 year	Supportive therapy (cases of meningitis) 200 mg once a day
Cryptococcal meningitis	200 mg twice daily	from 2 months to 1 year
Histoplasmosis	from 200 mg once a day to 200 mg twice daily	8 months
Sporotrichosis	100 mg once a day	3 months
Paracoccidioidomycosis	100 mg once a day	6 months
Chromomycosis	100-200 mg once a day	6 months
Blastomycosis	from 100 mg once a day to 200 mg twice daily	6 months

Orunit (Orunit)